Adhesion molecules and cytokines
The bone marrow microenvironment has a very close symbiotic relationship with myeloma cells supporting their growth, development and survival, and also playing an important role in causing drug resistance. Watch the following animation which reviews the myeloma cell and cytokine interactions in the bone marrow microenvironment.
The microenvironment is composed of a cellular compartment comprising haematopoietic cells and non-haematopoietic cells such as fibroblasts, endothelial cells (collectively referred to as stromal cells), osteoclasts and osteoblasts, and a non-cellular compartment comprising the extracellular matrix and the liquid milieu including cytokines and growth factors (Figure 7).
Myeloma cells home in on the bone marrow and adhere to the extracellular matrix proteins, the stromal cells and to each other, sometimes forming tumour-like masses throughout the bone marrow. The cytokines they secrete act on the bone cells while the cytokines and growth factors from the bone marrow milieu stimulate myeloma cell growth. Of these, interleukin- 6 (IL-6) is arguably the most important cytokine in myeloma. It is primarily produced by stromal cells and osteoblasts and is key in mediating myeloma cell growth through what is known as a paracrine mechanism. IL-6 is also secreted by myeloma cells themselves in what is known as an autocrine mechanism to stimulate its own growth.
IL-6 has also been implicated in the resistance of myeloma cells to a number of stimuli for cell death and is a major determinant of myeloma cell response to chemotherapy. It is also an example of a therapeutic target of the support system myeloma cells rely on to survive.
Other cytokines, including vascular endothelial growth factor (VEGF), TNF-α and transforming growth factor-beta (TGF-β), secreted by myeloma cells and bone marrow stromal cells further increase the secretion of IL-6.
Figure 7: Interaction of myeloma cells with adhesion molecules in the bone marrow microenvironment
Cell surface adhesion proteins (sometimes known as adhesion molecules) also play an important role in establishing the growth and development of myeloma cells within the bone marrow. Their presence on the surface of myeloma cells is necessary for binding to stromal cells. Several types of adhesion molecules exist (e.g. VLA-4, LFA-1, VCAM, ICAM, syndecan, CD40).